While significant study has been directed at understanding the genetic basis of cancer, there is growing vidence that epigenetic mechanisms also play a significant role. Epigenetic mechanisms, such as hromatin modifications and DNA methylation, are stable, long-term (typically heritable) changes in the ranscriptional potential of a cell that are independent of changes in the underlying genomic sequence. These epigenetic modifications can reveal the transcriptional history and key control mechanisms for protein-coding and miRNA genes. T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder of lymphoblasts arising in the T-cell lineage. The major subtype of human T-ALL can be defined by cytogenetic abnormalities and differentiation arrest at different stages of T-cell development. NOTCH1 serves as a unifying target in this model, as activating NOTCHI mutations have now been found in all of the most common subtypes of T-ALL and in more than 50% of all pediatric T-ALL cases. Our central hypothesis is that comparing the genome-wide epigenetic signatures of T-ALL cells to normal T cell precursors will lead to substantial new insights, including the identification of genes that are differentially regulated, as well as putative markers that might lead to early diagnosis and/or improved monitoring of the progress of tumor therapies. We propose to determine the dynamic changes to cell potential using high-quality epigenetic signatures of chromatin modifications and transcriptional potential during mammalian T cell development and leukemogenesis using a NOTCH-induced mouse model (AIM 1) to determine the epigenetic mechanisms involved in progression of the T-cell leukemias. Information gathered using the mouse models will complement epigenetic state of specific subtypes of human T-ALL with defined genetic mutations (TAL1 pos, +/- NOTCH mutations) (AIM 2). The long-range goal of this proposal is to identify the transcriptional history and key epigenetic control mechanisms genome-wide for all protein-coding and miRNA genes during mammalian T cell development and T cell leukemogenesis and thus provide a critical signature of leukemic identity.

Public Health Relevance

T-Acute lymphoblastic leukemia (T-ALL) is characterized by a block in differentiation of T-cell progenitors, and an accumulation of immature lymphoblasts. Together with genetic changes, epigenetic alterations such as aberrant DNA methylation play a role in the molecular pathogenesis of the disease. Identifying the epigenetic mechanisms dysregulated in T-ALLmay lead to new epigenetic biomarkers and therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA109901-09
Application #
8454438
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$377,438
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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